INTRA-UTERINE RING FOR THE RELEASE OF AN ACTIVE AGENT, SUCH AS A HORMONE, AND AN INTRODUCER

Abstract: The invention relates to an intra-uterine ring (12) for the release of an active agent, having a closed or an open configuration and having attached to it a thread (11) for the removal of the ring. The ring is fabricated of an elastic polymeric material, in which the active agent is mixed. The invention also relates to an introducer for the insertion of the ring into the uterus. The intruducer comprises an elongated main body (15), a handle (17) and a locking device (19) for the locking into position of the tightened removal thread.

Description: Intra-uterine ring for the release of an active agent, such as a hormone, and an introducer. This invention relates to an intra-uterine ring for the release of an active agent such as a hormone, said ring having either a closed or an open configuration and being fabricated from an elastic polymeric material with the active agent mixed therein. The invention also relates to an introducer for the positioning of the device. An intra-uterine contraceptive device in general use is a plastic body in "T" form having, partly coiled around it, a copper thread capable of releasing copper ions . The device is inserted into the uterine cavity by means of a separate introducer. The device has an attached thread long enough to protrude from the uterine cervix when the device is in place. Prior art discloses also different intra-uterine hormone- releasing devices not in the form of a ring. US 3656483 describes an IUD (intra-uterine device) having outwardly projecting wings when positioned. US 4014988 describes hormone-releasing IUDs in which the active substance is dissolved in a liquid carrier contained in a reservoir. The coating surrounding the reservoir is made of a suitable polymer. The IUDs are not in the form of a ring but in the form of a "T", "7" or "S". US patents 4264575 - 4264578 all relate to IUDs with the active agent dispersed in a silicone polymer. No configurations for the devices are disclosed in these patents, which instead refer to devices described in previous US patents. None of the patents referred to relate to a unit ring, instead they relate to totally different configurations. US 3896819 relates to a device for intra-uterine use, which may for instance have the form of an "8", and in which the active substance is in solution in a reservoir, from which it is released by diffusion through a membrane. US 4180064 relates also to an intra-uterine device, for instance in the form of an "8", wherein the active agent is dispersed in a biodegradable polymer. US 4871543 and US 4888074 both relate to rings having a core consisting of an active agent (hormone or other) dispersed in a polymer, e.g. a polysiloxane, and surrounded by a membrane of e.g. silicone, containing no active agent. These rings are however for intra-vaginal use, and the patents contain no mention of or reference to the suitability of the said rings also for intra-uterine use. Devices in the form of a "T" or any other form other than ring, having sharp parts, may cause pain to the wearer or even damage to uterine wall. The devices described in US patents 3896819 and 4180064 have no practical use. The system described in US patent 3896819 involves great risks: in case of rupture of the reservoir in which the active agent is dissolved the whole amount of the drug would be released and would cause a state of intoxication to the wearer. For the ensurance of the integrity, during insertion, of this kind of reservoir, it must be rather rigid in form. This could easily damage the uterine cervix during insertion and removal of the device. The ring based on a biodegrable polymer, described in US patent 4180064, would not be practicable. Biodegradable polymers are hard and inflexible, which would make it very difficult to introduce rings made of such material. If the ringlike structure of the device is broken during the degradation process it could be extremely difficult to remove the device, because it would be deformed and its hard, broken parts would cause tissue damage . The objective of this invention is to overcome the disadvantages of the devices referred to supra and to achieve a novel intra-uterine ring for the release of an active agent, said ring being fabricated of a highly flexible polymeric material, in which the active agent is mixed. The invention thus relates to an intra-uterine ring for the release of an active agent, the said ring having either a closed or an open configuration, and having an attached thread for removal. The ring is characterized by being fabricated of an elastic polymeric material, in which the active agent is mixed. The invention also relates to an introducer for the insertion into the uterus of a ring defined in this invention. The introducer is characterized by consisting of: - an elongated main body whose leading end (pointing to fundus uteri) conforms to the shape of the external coating of the ring in such a way that the ring is retained in the shaped end piece during the insertion of the ring, - a handle in the trailing end of the main body, and - outside the handle, on the opposite side, a locking device for the locking into position of the removal thread when tightened. A ring as defined in the present invention can, if desired, be coated with a separate polymeric membrane regulating the release rate of the active agent. The polymeric membrane can be made of the same or a different polymer or mixture of polymers as the polymer matrix incorporating the active agent. It is essential that the polymer used for both the matrix and the membrane is highly flexible, and for this reason silicone polymers are particularly well suited. A ring according to the present invention is in principle suitable for dispensing any active agent. The device is however specifically designed for hormone release for the treatment of menopausal symptoms or for contraception. The appropriate hormones in that case are the oestrogens and the progestins. A ring according to the present invention may have either a closed or a slightly open configuration. For instance, when applying the fabrication method described in US patent 4888074 open rings are produced by cutting the spiral extrudate in the direction of the axis of the reel. Individual open rings may be closed if desired but they can also be used as such. A ring according to the present invention may be for instance circular, oval, ellipsoidal or curved in some other form. The cross-section of a ring as defined in the present invention may be for instance circular, oval, ellipsoidal or in some other suitable form. A disadvantage of a circular cross-section is that the release rate of the active agent falls with time due to the fact that the diffusion distance of material located in the centre of the ring is considerably longer than the diffusion distance of material located in the vicinity of the periphery. To achieve an active agent release rate as even as possible, the cross-section may be designed in such a form that the diffusion distance of the active agent from different points of the cross-section to the periphery is essentially the same. A prefereble form of cross-section is a star, for instance a star with four points, the said points being slightly rounded to avoid tissue damage. The form of the cross-section is important mainly in such rings whose polymerix matrix incorporating the active agent is not coated with a separate membrane. If, on the other hand, a separate polymeric membrane is used, it will regulate the release rate of the active agent. The most preferable type of a ring according to the invention has an external diameter of about 18 mm, with the diameter of the cross-section of the ring being about 1.5 mm. Due to the exceptional flexibility of a ring according to the present invention it is easy to introduce the ring also into the uterine cavity of menopausal women, who have a narrow uterine cervix. Very small introducers may also be made. The invention will be illustrated in more detail by the following figures, where Fig. 1 is a view of a ring of the present invention, positioned in the uterus Fig. 2 is a view of an introducer used for the insertion of a ring of the present invention Fig. 3 illustrates another embodiment of an introducer for the insertion of a ring of the present invention Figs. 4 - 7 illustrate the insertion of the ring Fig. 8 illustrates one embodiment of the cross-section of the ring The ring 12 has, attached to it, a thread 11 for removing the ring, surrounding the outer coating of the ring 12 in such a way that the trailing ends 11' and 11'' of the thread are long enough to allow locking of the said ends, during insertion, in the locking device 19. After insertion, the ends of the threads may be shortened somewhat, but it is recommended to leave them long enough for them to be visible outside the uterine cervix even when the device has been positioned in the womb 10. The device may then be manually removed. Fig. 2 illustrates an introducer for the insertion of the ring, having an elongated main body 15 consisting of a tube comprising a channel 16. The handle 17 of the introducer forms an integral unit with the body 15. Handle 17 also has a channel 16' running through it and being suitably a continuation of channel 16. The end piece 18 of the main body 15 is so shaped that ring 12 abutting onto it will remain in position after the trailing ends 11' and 11'' of the thread have been tightened and locked into position with the locking device 19, which in this drawing is only presented schematically. A fragmented view is shown of ring 12, whose cross-section 22 in the example presented herein is circular. Channels 16 and 16' may be run as tubes inside the parts 15, 17 or they may be grooves made in them. Fig. 3 illustrates another embodiment of the introducer, in which the main body 15 is in the form of a rod. The leading end 18 of the rod is so shaped as to support the ring 12. The end piece 18 preferably incorporates a channel 20, which may be a tube or a groove, for the passage of the removal thread. Tightening and lockimg of the trailing ends 11' and 11'' of the thread is achieved in the same manner as in the embodiment illustrated in Fig. 2. Alternatively the ring may be positioned at the end piece of the rod in such a way that the attachement point of the thread will be located opposite to end piece 18. The ring will be put into this position by rotating the ring illustrated in Fig. 3 by 180°. By pulling at the thread the ring can be pre-tightened prior to the insertion of the introducer and the attached ring into the uterus, so imparting a rectangular form to the ring in the manner shown in Fig. 7. Figs. 4 - 7 illustrate the positioning of the ring 12 in the uterus. The trailing ends 11' and 11'' of the threads are tightened and locked into position with the locking device 19, the ring thus abutting onto the end piece 18 of the introducer. The introducer is pushed through the uterine cervix up to the point where the limiting mark 21 in the body of the introducer, between the handle 17 and the end piece of the body 18 indicates that the ring is positioned in the upper part of the uterus. The tension of the ends 11' and 11'' of the thread is released by freeing the ends of the thread from the locking device. The introducer is pulled off and the ring remains in the uterus. It will be appreciated from Figs. 5 and 7 that the ring is highly flexible. The periphery of the ring can be, by a slight compression or a pulling force, shaped essentially into the form of a rectangle, whose long sides 12' and 12'' approach each other very closely. Fig. 4 illustrates the introduction of a ring without pretightening. Fig. 7 illustrates the introduction of a pretightened ring. Fig. 8 illustrates a preferable embodiment of the cross- section 22, i.e., a star with four points slightly rounded to avoid tissue damage. The polymers and active agents employed for a ring of the present invention are components generally used for vaginal rings. The passage of an active substance within the polymeric matrix and the rate of its release through the polymeric membrane follow the same patterns as in vaginal rings known to the art, described e.g. in US patent 4871543. Those versed in the art will appreciate that many different variations and adaptations of the present invention fall within the scope of the claims to be presented in the following section.

Claims: CLAIMS 1. An intra-uterine ring (12) for the release of an active agent, the said ring having either a closed or an open configuration and having, attached to it, a thread (11) for removal of the ring, characterized by fabrication of the ring from an elastic polymeric material, in which the active substance is mixed. 2. A ring defined in claim 1 characterized by coating the ring with a separate polymeric layer regulating the release rate of the active substance. 3. A ring defined in claim 1 or 2 characterized by such elasticity of the ring (12) that the periphery of the said ring (12) can be shaped by slight compression or a slight pulling force into a form essentially of a rectangle having its long sides (12', 12'') approaching each other very closely. 4. A ring defined in claim 1, 2 or 3, characterized by the polymeric material being a silicone polymer. 5. A ring defined in claim 1, 2, 3 or 4, characterized by the active substance being a hormonal agent suitable for treatment of menopausal symptoms or for contraception. 6. A ring defined in claim 5 characterized by the hormonal agent being an oestrogen or a progestin. 7. A ring defined in any of the claims 1 - 6 characterized by the shaping of the cross-section (22) of the ring, in order to achieve a release rate of the active agent as even as possible, into a form allowing an essentially equal distance of passage of the active agent from different points in the cross-sectional plane to the periphery of the cross-section. 8. A ring defined in claim 7 characterized by the cross- section (22) being essentially in the form of a star, preferably a star with four points, said points being slightly rounded. 9. An introducer for the insertion into the uterus of the ring defined in any of the claims 1 - 8, characterized by comprising an elongated main body (15), whose leading end (18), pointing to the fundus uteri, is shaped to adapt to the outer coating of the ring so as to retain the ring in the said shaped end during the introduction of the ring; a handle (17) in the trailing end of the main body, away from the uterus; and on the side opposite to the handle (17), a locking device (19) for the locking into position of the tightened removal thread (11, 11', 11''). 10. An introducer as defined in claim 9 characterized by the main body (15) consisting of a tube having a channel (16) for the passage of the thread for manual removal. 11. An introducer as defined in claim 10 characterized by the main body (15) and handle (17), which also has a channel for the passage of the removal thread, forming a unit piece. 12. An introducer as defined in claim 9 characterized by the main body (15) being a rod. 13. An introducer as defined in claim 12 characterized by the leading end (18) of the rod-like main body (15) having a channel (20) for the removal thread and by the handle at other end of the rod-like main body also having a channel for the passage of the removal thread.

Inventors: LEHTINEN MATTI, LEHTINEN, MATTI
Applicants: LEHTINEN MATTI, LEIRAS OY, LEHTINEN, MATTI
Application year: 1994
Main classification: A61K9
IPC codes: A61F6, A61K9, A61M31